Infectious Diseases

Botulism

OVERVIEW: What every practitioner needs to know

Are you sure your patient has botulism? What should you expect to find?

Most patients with botulism present with cranial nerve dysfunction; difficulty swallowing, dysarthria, blurred vision and diplopia are among the most common early complaints. Weakness of the upper extremities usually follows these problems related to cranial nerves, followed by lower extremity weakness. Respiratory failure may occur at any time because of upper airway weakness, inability to handle secretions, or weakness of the diaphragm or parasternal intercostal musculature. Botulism itself produces constipation, but the patient may initially complain of diarrhea, nausea, and vomiting after ingestion of improperly prepared or preserved food.

The most common physical findings on presentation include ptosis, ophthalmoparesis, weakness of the tongue, symmetric facial paresis, and extremity weakness. However, each type of botulism affecting humans has a different constellation of findings. Infants with botulism are floppy and have weak cries and difficulty feeding.

How did the patient develop botulism? What was the primary source from which the infection spread?

Botulism is a consequence of intoxication with botulinum toxin. Each of the major forms of botulism has a different source of toxin. Eating inadequately prepared food results in ingestion of the toxin. Infant botulism and adult gastrointestinal botulism follow ingestion of ubiquitous spores of Clostridium botulinum, which then germinate and produce toxin within the gut. Wound botulism follows inoculation of spores into tissues, typically by injection drug use but potentially from any wound. Inhalation botulism would imply bioterrorism unless acquired in a laboratory setting. Rarely, patients who have received therapeutic injections of botulinum toxin develop systemic signs of botulism. There remain a few cases in which the site of toxin or spore entry remains unknown.

Foodborne botulism typically occurs in small common-source outbreaks. Infant botulism was associated with honey ingestion, but other sources of spores are still present in the environment.

Which individuals are of greater risk of developing botulism?

Since immunization against botulism is not commonly available, everyone is susceptible to the foodborne form. Infants, and adults who lack or suppress gastric acid production, are at risk of gastrointestinal colonization and local toxin production. Anyone could develop botulism after a wound, but most cases are seen with injection drug users who inject the spores into tissues.

Beware: there are other diseases that can mimic botulism:

Myasthenia gravis and the Lambert-Eaton myasthenic syndrome are the major differential diagnostic concerns in cases of possible botulism. The Miller Fisher variant of the Guillain Barré syndrome, while quite rare, closely mimics the cranial nerve findings of botulism, and since it may follow a diarrheal illness the prospect of a food-borne disease is apparent. Tick paralysis involving Dermacentor ticks produces a similar disease.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

There are no routine laboratory tests that will aid in the diagnosis or differential diagnosis of botulism.

The best bedside study is repetitive nerve stimulation at high frequency (20 Hz or greater). Patients with presynaptic acetylcholine release defects (botulism or the Lambert-Eaton myasthenic syndrome) will have an incremental muscle response to this stimulation. Patients with myasthenia gravis (a post-synaptic disorder) classically have a decremental response. However, at the lower frequencies (e.g., 4 Hz) used for the diagnosis of myasthenia gravis, patients with botulism may show no change, or even a decrement, so high frequency stimulation must be requested when botulism is considered.

Results that confirm the diagnosis

The diagnosis is confirmed by recovery of toxin from the serum or stool; this is still done using a mouse assay. In suspected inhalation botulism, toxin may also be recovered from nasal secretions. Anaerobic cultures of food or stool which grow C. botulinum are supportive, but since the spores are ubiquitous, they are not diagnostic. Anaerobic cultures of debrided wound tissue would also be diagnostic.

What imaging studies will be helpful in making or excluding the diagnosis of botulism?

There are no imaging studies of value in this condition.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has botulism, what therapies should you initiate immediately?

Heptavalent human botulinum antitoxin is available through the Centers for Disease Control and Prevention (CDC). A separate antitoxin for infants (babyBIG) is available from the California Department of Public Health.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Antibiotics are not indicated for botulism due to toxin ingestion or inhalation. In cases of gastrointestinal or wound botulism, penicillin G or metronidazole may be administered, but antitoxin should still be given. Antibiotics are not usually advised in infant botulism. Aminoglycosides, macrolides, and tetracyclines should not be used, since they can further impair neuromuscular transmission by interfering with calcium entry into neurons.

2. Next list other key therapeutic modalities.

Endotracheal intubation and mechanical ventilation are required for airway or ventilatory compromise. Since recovery may take months, consider early tracheostomy for patient comfort.

Swallowing dysfunction may require placement of a feeding tube. If a tracheostomy is undertaken, consider placement of a percutaneous endoscopic gastrostomy tube.

What complications could arise as a consequence of botulism?

What should you tell the family about the patient's prognosis?

The mortality rate for adults with botulism is about 5%. The first case in an outbreak usually has the highest likelihood of death, as the diagnosis may not be considered and the patient may suffer ventilatory failure before the severity of the condition is recognized. Once an outbreak is recognized, the mortality rate falls, and the risk of death then depends primarily on intensive care unit complications (e.g., pulmonary embolism) and co-morbid conditions. The mortality of infant botulism is less than 1%.

Patients make the majority of their improvement during the first three months of illness. However, they can continue to improve slowly thereafter for up to a year.

How do you contract botulism and how frequent is this disease?

In the US, between 20 and 45 cases of botulism are reported annually.

What pathogens are responsible for this disease?

Almost all cases of botulism are caused by C. botulinum, although rare examples of other Clostridia producing botulinum toxin have been described (e.g., C. baratii, C. butyricum).

How do these pathogens cause botulism?

Botulinum toxin is a zinc-dependent metalloproteinase which is synthesized as a single chain and then nicked to produce a heavy chain and a light chain. The heavy chain allows the toxin to bind to its putative receptor on the presynaptic neuron of the neuromuscular junction (or an autonomic synapse for the eye and the gut). The toxin is internalized via receptor-mediated endocytosis, and then released into the cytoplasm. The light chain interacts with the synaptic vesicle release mechanism that is responsible for coupling the increase in intracellular free calcium (caused by depolarization of the presynaptic neuron), inhibiting one of the several proteins involved in transmitter release.

Each toxin type targets an individual component of the release mechanism. All of the manifestations of botulism stem from this effect, with the motor manifestations resulting from inhibition of transmitter release at the neuromuscular junction, and the ocular and gastrointestinal effects a consequence of muscarinic synaptic inhibition. The toxin also affects transmission in autonomic ganglia, although the contribution of this effect to its clinical manifestations is uncertain.

Recovery from botulism first involves the development of new neuromuscular junctions and synapses. After several months, transmission recovers at the original sites, and the new connections are pruned away.

What other clinical manifestations may help me to diagnose and manage botulism?

A history of other affected individuals makes botulism more likely. If the individuals involved had vomiting and diarrhea as a premonitory phase of their illness (due to a different toxin, such as staphylococcal toxin A), then foodborne disease is quite likely. Conversely, if a group of people present nearly simultaneously, with constipation as their gastrointestinal complaint, the clinician should consider a bioterrorist event, either inhalation or adulteration of food with toxin.

Patients with myasthenia gravis will usually have a long history of less severe weakness and diplopia before they come to medical attention. Myasthenia is not associated with pupillary dilation, so blurred vision is not an issue in this condition, but the patient with slight diplopia may report this as blurring. Myasthenic patients do not have gastrointestinal complaints.

The same muscle groups tend to be involved in botulism and myasthenia gravis, but the presence of dilated pupils indicates botulism rather than myasthenia. Patients with the Lambert-Eaton myasthenic syndrome tend to have small, poorly reactive pupils. Deep tendon reflexes may be diminished in either botulism or Lambert-Eaton syndrome, but are usually normal in myasthenia.

What other additional laboratory findings may be ordered?

Patients with myasthenia usually have either anti-acetylcholine receptor antibodies or, less commonly, antibodies against muscle-specific kinase. Patients with the Lambert-Eaton myasthenic syndrome usually have antibodies directed at the P/Q-type calcium channel. However, by the time the results of these studies are available, the diagnosis of botulism has usually been established or refuted.

How can botulism be prevented?

Although there is an experimental vaccine for laboratory workers and members of the military, there is no vaccine for civilians. Thus, proper food handling is the most important preventive measure. Botulinum spores are relatively resistant to heat, including boiling, but will be destroyed in a properly operated pressure cooker. Importantly, the toxin is denatured by cooking at 85ºC. Avoiding honey has decreased cases of infant botulism by about 50%, but the sources of spores in the remaining cases have proved elusive.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

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